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CASE REPORT
Year : 2020  |  Volume : 68  |  Issue : 5  |  Page : 1217-1219

Brown–Vialetto–Van Laere syndrome: A rare case report of MND mimic


Department of Neurology, Andhra Medical College, Visakhapatnam, Andhra Pradesh, India

Date of Web Publication27-Oct-2020

Correspondence Address:
Dr. Butchi Raju Garuda
Department of Neurology, 2nd Floor, Superspeciality Block, King George Hospital, Andhra Medical College, Maharanipeta, Visakhapatnam - 530 002, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.299175

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 » Abstract 


Brown‐Vialetto‐Van Laere Syndrome (BVVLS) is a rare disorder characterized by progressive neuropathy, optic atrophy, hearing loss, bulbar dysfunction, and respiratory insufficiency associated with mutations in SLC52A2 and SLC52A3 genes that code for human riboflavin transporters RFVT2 and RFVT3, respectively. Nearly 70 cases have been reported by molecular diagnosis.[2],[3] The majority of familial cases are autosomal recessive[2],[4] with female to male ratio of 3:1.[5] We describe the clinical course of a 16-year-old boy with BVVLS who presented with 6 years duration of insidious onset gradually progressive sensory neural hearing loss, optic atrophy, amyotrophy of both upper limbs, and wasting of the tongue with fasciculations. Novel homozygous mutation c.1245C>T in the SLC52A2 gene was identified. At times, the clinical spectrum mimics the juvenile onset motor neuron disease (MND) as in this case. It was important to identify the BVVLS that can respond to high doses of riboflavin.


Keywords: Brown–Vialetto–Van Laere syndrome, deafness, motor neuron disease, optic atrophy, riboflavin transporter deficiency, SLC52A2
Key Message: BVVLS is a rare disorder which can mimic MND of young onset and responsive to high doses of Riboflavin. So, it is important to identify this disorder at the earliest to prevent progression.


How to cite this article:
Kranthi P, Garuda BR, Gopi S, Kumar T S. Brown–Vialetto–Van Laere syndrome: A rare case report of MND mimic. Neurol India 2020;68:1217-9

How to cite this URL:
Kranthi P, Garuda BR, Gopi S, Kumar T S. Brown–Vialetto–Van Laere syndrome: A rare case report of MND mimic. Neurol India [serial online] 2020 [cited 2020 Dec 2];68:1217-9. Available from: https://www.neurologyindia.com/text.asp?2020/68/5/1217/299175




Brown-Vialetto-Van Laere Syndrome (BVVLS) is a rare neurodegenerative disorder first described in 1894 by Brown later by Vialetto in 1936 and Van Laere in 1966.[1],[2],[3] Mutations causing BVVLS were seen in SLC52A2 (formerly C20orf54, encoding RFVT2) or SLC52A3 (encoding RFVT3).[4],[5],[6] Mutations in both the genes result in riboflavin transporter defect that was at least partially responsive to riboflavin supplementation.[7]

The typical clinical features of both forms are progressive axonal neuropathy with predominant upper limb and axial involvement in RFVT2 compared to generalized weakness in RFVT3, and a prominent sensory ganglionopathy and sensory ataxia in RFVT2, optic atrophy, sensorineural hearing loss, bulbar dysfunction, and respiratory insufficiency.[8] At times, the clinical presentation mimics motor neuron syndrome.[7],[8] The following case highlights the clinical features of BVVLS and the identification of novel mutations in SLC52A2.


 » Case Report Top


A 16-year-old boy, a product of nonconsanguineous parentage with normal development and family history, presented with gradually progressive hearing loss of 6 years duration. There is also history of defective vision in both eyes since last five years more on left side. At the time of presentation to our hospital, he could see objects at the distance of 3 m with the left eye and 5 m distance with the right eye. Noticed distal weakness of both upper limbs since two years and thinning of small muscles of hands from eight months. There was no history of proximal weakness in the upper limbs, lower limbs, neck, or trunk. No cranial nerve involvement or history suggestive of sensory, cerebellar, bowel, or bladder involvement was observed.

Upon neurological examination, there was bilateral decreased visual acuity, and fundus examination revealed optic atrophy. There was also bilateral sensory neural hearing loss (SNHL), atrophic tongue with fasciculations, wasting of small muscles of hand with split hand sign and distal weakness of both upper limbs with poly-mini myoclonus [Figure 1]. Reflexes were absent in upper limbs and brisk in lower limbs with ankle clonus and plantar reflexes were mute with no sensory deficit. Marfanoid features (wrist and thumb sign) were noted. The rest of the examination was normal.
Figure 1: Wasting of forearms and hands with clawing of fingers

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Routine laboratory tests, peripheral smear, and toxic profile were normal. Magnetic resonance imaging (MRI) scan of the brain and cervical spine were normal [Figure 2] and [Figure 3]. Nerve conduction studies showed diminished amplitudes of compound muscle action poltentials (CMAPs) with normal SNAPs. Electromyography (EMG) revealed a neuropathic pattern with chronic denervation and reinnervation changes in C6 to T1 segments.
Figure 2: Magnetic resonance imaging scan of the cervical spine

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Figure 3: Magnetic resonance imaging scan of the brain

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Next-generation sequencing revealed homozygous variation in exon 5 of the SLC52A2 gene [chr8: 145584582C>T; c.1245C>T] that resulted in the synonymous amino acid change of glycine at codon 415 [p. Gly415(=)] and was being validated by Sanger sequencing. So, the patient was called for a follow-up and started on 25 mg/kg of riboflavin. There was no significant change in neurological status at 6 months of follow-up.


 » Discussion Top


One study identified 18 patients from 13 families with mutations in SLC52A2.[1] To the best of our knowledge, the c.1245C>T in exon 5 of SLC52A2 found in our patient was not reported in the literature.

In our patient, SNHL is the first symptom followed by optic atrophy, amyotrophy of distal upper limbs, atrophic tongue with fasciculations, and a phenotype consistent with SLC52A2 mutation, which was in contrast to generalized weakness in SLC52A3 mutation. Upper motor neuron involvement is less frequent.[5] However, our case had brisk reflexes in lower limbs and ankle clonus. He also had marfanoid features, which were not described previously. Bulbospinal muscular atrophy with deafness was first reported in India as BVVLS in 1996.[9] Phenotypic presentation like an MND with deafness and optic nerve involvement of childhood-onset was well-described.[10] So, BVVLS should be a differential diagnosis of juvenile-onset MND as it was a potentially treatable condition.

There were no MRI changes in this patient although others reported atrophy of the brainstem and cerebellum[11] and increased signal on T2 sagittal views of the cervical spinal cord, with subtle changes affecting the dorsal columns.[8]

Several conditions closely resemble BVVLS that should always be considered in the differential diagnosis. The most closely related disease is the Fazio–Londe syndrome, where the only distinguishing feature is the absence of deafness.[10] Another differential is the Nathalie syndrome, which is a rare condition characterized by deafness in conjunction with spinal muscular atrophy, cataract, cardiac conduction defects, and hypogonadism. The Boltshauser syndrome, which mimics BVVLS, is characterized by distal muscular atrophy with vocal cord paralysis and SNHL. However, in the former, the brainstem signs are restricted to vocal cord paralysis. The Madras pattern of MND was another close differential presenting with wasting and weakness of limb muscles, sensory neural hearing loss, along with VII, IX and XII cranial nerve involvement.[8],[10]

The exact pathophysiology of the neuropathy in BVVLS and the process by which riboflavin deficiency causes sensory and motor neuron degeneration remains to be clarified. Preliminary human tissue studies of the SLC52A2 encoded RFVT2 demonstrate a relatively higher expression in the brain and spinal cord than in the small intestine. Significant clinical and biochemical improvements were observed after the initiation of high-dose oral riboflavin therapy in patients with mutations in SLC52A2.[6],[7],[8] Dramatic improvement of vision has been recently reported even after delayed riboflavin therapy.[12] Our patient did not have any significant recovery with riboflavin therapy after 6 months of follow-up.

It is the timely consideration of a diagnosis of a riboflavin transporter deficiency and the rapid initiation of high-dose riboflavin therapy, in any child presenting with a rapidly progressive motor axonal neuropathy particularly in association with optic atrophy, bulbar dysfunction, hearing loss, or respiratory insufficiency might prevent and reverse the progression of this hitherto elusive and relentlessly progressive neurodegenerative condition.


 » Conclusion Top


This case identifies a novel mutation for BVVL syndrome and emphasizes the need for early diagnosis and management of symptoms, which can lead to improved clinical outcomes in patients with this disease. This case also highlights the presence of a juvenile-onset MND with deafness. So, BVVLS should be considered as a differential diagnosis in all such cases as it is potentially responsive to high doses of riboflavin.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgement

We acknowledge the Med Genome Labs, Bangalore for conducting the genetic study of this case at a very concessional price.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Sathasivam S. Brown–Vialetto–Van Laere syndrome review. Orphanet J Rare Dis 2008;3:9.  Back to cited text no. 1
    
2.
Me'garbané A, Desguerres I, Rizkallah E, Delague V, Nabbout R, Barois A, et al. Brown–Vialetto–Van Laere syndrome in a large-inbred Lebanese family: Confirmation of autosomal recessive inheritance? Am J Med Genet 2000;92:117-21.  Back to cited text no. 2
    
3.
Camargos S, Guerreiro R, Mageste LS. Late-onset and acute presentation of Brown-Vialetto-Van Laere syndrome in a Brazilian family. Neurol Genet 2018;4:e215:1-3.  Back to cited text no. 3
    
4.
De Grandis D, Passadore P, Chinaglia M, Brazzo F, Ravenni R, Cudia P. Clinical features and neurophysiological follow-up in a case of Brown–Vialetto-Van Laere syndrome. Neuromusc Disord 2005;15:565-8.  Back to cited text no. 4
    
5.
Voudris KA, Skardoutsou A, Vagiakou A. Infantile progressive bulbar palsy with deafness. Brain Dev 2002;24:732-5.  Back to cited text no. 5
    
6.
Foley AR, Menezes MP, Pandraud A, Gonzalez MA, Al-Odaib A, Abrams AJ, et al. Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain 2014;137:44-56.  Back to cited text no. 6
    
7.
Bosch AM, Stroek K, AbelingNG, Waterham HR, Ijlst L, Wanders RJ. The Brown-Vialetto-Van Laere and Fazio Londe syndrome revisited: Natural history, genetics, treatment and future perspectives. Orphanet J Rare Dis 2012;7:83.  Back to cited text no. 7
    
8.
Woodcock IR, Menezes MP, Coleman L, Yaplito-Lee J, Peters H, White SM, et al. Genetic, radiologic, and clinical variability in Brown-Vialetto-van Laere Syndrome. Semin Pediatr Neurol 2017;26:2-9.  Back to cited text no. 8
    
9.
Rohatgi A, Mehandiratta MM. Bulbospinal muscular atrophy with deafness: Vialetto van-Laere syndrome. Neurol India 1996;44:231-3.  Back to cited text no. 9
[PUBMED]    
10.
Set KK, Weber ARB, Serajee FJ, Huq AM. Clinical reasoning: Siblings with progressive weakness, hypotonia, nystagmus and hearing loss. Neurology 2018;90:e625-31.  Back to cited text no. 10
    
11.
Koc AF, Bozdemir H, Sarica Y. Mental retardation associated with Brown–Vialetto–Van Laere syndrome. Amyotroph Lateral Scler Other Motor Neuron Disord 2003;4:52-3.  Back to cited text no. 11
    
12.
Ahmed K Bamaga, Robi NM, Susan MC, Marwan S, Paul TG. Child neurology: Brown-Vialette-Van Laere syndrome: Dramatic visual recovery after delayed riboflavin therapy. Neurology 2018;91:938-41.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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